Cartilage and chondrocytes undergo changes with aging including increased apoptosis and decreased response to growth factors. Age-associated changes occur in several joints including the temporomandibular joint as well as knee and hip and may predispose the cartilage to degenerative joint disease (osteoarthritis, OA). The molecular basis for these changes is not well-defined. Bag- 1(Bcl-2 athanogene-1) is a member of a protein family that interacts with Bcl-2 as well as heat shock proteins, growth factor receptors and steroid hormone receptors, and kinases. Bag-1 plays a key regulatory role in cellular activities such as apoptosis, proliferation, and response to growth factors. The overall hypothesis under study herein is that the Bag-1 protein is an important regulator of chondrocyte function and that changes in Bag-1 expression with age contribute to the tissue changes. The specific aims are integrated experiments designed to directly establish the Bag-1 protein expression pattern during cartilage aging and during age-associated cartilage disease and to define the precise pathways regulated by Bag-1 in chondrocytes under homestatic and stress conditions. Aim 1: Define the expression pattern of Bag-1 in articular cartilage using models of aging (aging mice, aging rats, senescence accelerated mice) and in relation to disease severity in human OA. Also, test the specific subhypothesis that the decline in Bag-1 expression with aging (or disease) is associated with increased endoplasmic reticulum (ER) stress. Aim 2: Identify the precise mechanisms by which Bag-1 regulates chondrocyte apoptosis and matrix protein expression under homeostatic and stress conditions. The basic approach will be to directly modulate Bag-1 levels in chondrocytes by over- expression and knockdown approaches with and without the induction of ER stress. The successful completion of these aims will provide information about the role of Bag-1 in chondrocyte biology. In addition these studies will help define a potentially novel molecular mechanism operating during cartilage aging and disease. Finally, the combination of the hypothesis-driven research plan with focused student involvement will provide a strong training component for the student trainees. of Proposed Research to Public Health Age-associated changes in cartilage lead to osteoarthritis which is one of the major causes of pain and suffering among our aging population. By identifying the specific changes that occur in cartilage during aging it will be possible to identify specific strategies to slow down or stop this process and reduce the impact of cartilage disease on society. [unreadable] [unreadable] [unreadable]